The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing
Open accessAbstract
Cellular senescence is a recognized mechanism of tumour suppression; however, its contribution to other pathologies is not well understood. We show that the matricellular protein CCN1 (also known as CYR61; cysteine-rich protein 61), which is dynamically expressed at sites of wound repair, can induce fibroblast senescence by binding to integrin α6β1 and the heparan sulphate proteoglycans (receptors involved in cell adhesion). CCN1 induces DNA damage response pathways and activates p53 and the RAC1–NOX1 complex, which generates reactive oxygen species (ROS). This results in the ROS-dependent activation of the p16INK4a/pRb pathway, leading to senescence and concomitant expression of antifibrotic genes. Senescent fibroblasts accumulate in granulation tissues of healing cutaneous wounds and express antifibrotic genes in wild-type mice. These processes are lost in knockin mice that express a senescence-defective Ccn1 mutant, resulting in exacerbated fibrosis. Topical application of CCN1 protein to wounds reverses these defects. Thus, fibroblast senescence is a CCN1-dependent wound healing response in cutaneous injury that functions to curb fibrosis during tissue repair.
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In skin, senescent cells clearly promote optimal wound healing.
“In the skin, for example, senescent cells clearly promote optimal wound healing (149).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [149]
The Results section reports that CCN1-induced senescent fibroblasts restrict excessive collagen deposition in healing mouse skin wounds, supporting a beneficial role. But it also reports that wounds with markedly fewer senescent cells closed somewhat faster, so the paper supports reduced fibrosis rather than an unqualified claim that senescent cells promote optimal wound healing overall. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn a mouse model of skin wounding, the injury induced cellular senescence, most likely in resident fibroblasts.
“Likewise, in a mouse model of skin wounding, the injury again induced cellular senescence, most likely in resident fibroblasts.”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [149]
The Results section reports that senescent cells accumulated in healing mouse wounds and identifies them as myofibroblasts; fibroblasts isolated from the wounds also showed senescence. It does not establish that those fibroblasts were resident cells rather than cells of another origin. No page number is available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCCN1/CYR61, an ECM protein that mediates senescence induction in the liver, promotes fibroblast senescence during cutaneous wound healing and limits skin fibrosis.
“Cellular communication network factor 1 (CCN1; also known as CYR61), an ECM protein that mediates the induction of cellular senescence in the liver, promotes senescence in fibroblasts during cutaneous wound healing, thus limiting skin fibrosis147.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [147]
The Introduction and Results identify CCN1 as CYR61 and report that it induces fibroblast senescence during cutaneous wound healing, curbing fibrosis. The paper does not establish that CCN1 mediates senescence in the liver: its Discussion says whether CCN1 is required for senescence in other organs is unknown. Page numbers were not available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredCellular senescence has beneficial roles in tissue remodelling during embryogenesis and wound healing.
“Cellular senescence, a stress-induced irreversible growth arrest often characterized by p16 Ink4a expression and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing.”
From Naturally occurring p16Ink4a-positive cells shorten healthy lifespan (2016) · cites this paper as [6]
The Discussion reports that CCN1-induced fibroblast senescence dampens fibrosis during cutaneous wound healing, supporting a beneficial role in tissue repair. Our copy does not address a beneficial role for senescence in tissue remodelling during embryogenesis (searched: embryogenesis, embryonic development). No page numbers are available in the indexed copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPresence of senescent human-derived cultured cells limits fibrosis during skin wound healing.
“The presence of senescent human- derived cultured cells limits fibrosis during skin wound healing 9”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [9]
The Results section ('CCN1-regulated senescence restricts fibrosis in cutaneous wound healing'; page unavailable) reports that senescent cells accumulated in mouse wounds and that CCN1-induced senescence curtailed collagen deposition. The paper also studied cultured human fibroblasts, but it does not show that those human-derived cultured cells were present in healing wounds or limited fibrosis there. (LLM, conf=0.90)
Experimental — accuracy not yet measured
CCN1 induces senescence by binding to integrin α6β1 to trigger a DNA damage response through p53- and p16INK4a/pRb pathways.
“Mechanistically, CCN1 induces senescence by binding to integrin α6β1 to trigger a DNA damage response through p53- and p16INK4a/pRb pathways (16).”
From Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 (2022) · cites this paper as [16]
The Discussion and Results sections (page numbers not provided) support CCN1 binding integrin α6β1 and inducing senescence through both p53 and p16INK4a/pRb. They describe the DNA damage response as activating p53, while the p16INK4a/pRb pathway is induced through ROS-dependent ERK and p38 MAPK signaling. The claim conflates these routes by implying that the DNA damage response proceeds through both pathways. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMatrix metalloproteinases that comprise the SASP were proposed to facilitate tissue repair by promoting collagen degradation, thereby limiting fibrosis.
“and the matrix metalloproteinases that comprise the SASP (Coppé et al., 2008, 2010b) were proposed to facilitate tissue repair by promoting collagen degradation, thereby limiting fibrosis (Jun and Lau, 2010; Krizhanovsky et al., 2008).”
From An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA (2014) · cites this paper as Jun and Lau, 2010
Experimental — accuracy not yet measuredSenescent stromal cells help resolve excessive fibrosis after skin or liver injury.
“Senescent stromal cells were shown to help resolve excessive fibrosis after skin or liver injury (Jun and Lau, 2010; Krizhanovsky et al., 2008).”
From An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA (2014) · cites this paper as Jun and Lau, 2010
Activation of CCN1 was shown to induce senescence during skin and liver repair.
“activation of the matricellular protein CCN1 was shown to induce senescence during skin and liver repair (Jun and Lau, 2010; Kim et al., 2013).”
From An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA (2014) · cites this paper as Jun and Lau, 2010
Recent reports showed a beneficial role for the SASP during embryonic development and in limiting fibrosis after tissue injury.
“recent reports showed a beneficial role for the SASP during embryonic development (Muñoz-Espín et al., 2013; Storer et al., 2013) and a role in limiting fibrosis after tissue injury (Jun and Lau, 2010; Krizhanovsky et al., 2008).”
From An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA (2014) · cites this paper as Jun and Lau, 2010
This signaling cascade induced both a senescence growth arrest and expression of several genes encoding SASP proteins.
“This signaling cascade induced both a senescence growth arrest and the expression of several genes that encode SASP proteins.”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [149]
In mice engineered to express a mutant CCN1 protein defective in integrin binding and inducing senescence, wounds were deficient in senescent cells and SASP gene expression.
“In mice engineered to express a mutant CCN1 protein that is defective in integrin binding and hence in inducing senescence, the wounds were deficient in senescent cells and SASP gene expression.”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [149]
Wounds in these mutant CCN1 mice healed with significantly more fibrosis.
“Importantly, wounds in these mice healed with significantly more fibrosis (149).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [149]
In that skin wound model, the senescence response was induced by a signaling cascade initiated by binding of CCN1 to its integrin receptor on target cells.
“In this case, the senescence response was induced by a signaling cascade that was initiated by the binding of CCN1, a matricellular protein, to its receptor, an integrin, on the surface of the target cells (149).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [149]
Senescent cells have beneficial effects in injury repair and tissue remodelling.
“Furthermore, recent studies showing that senescent cells have beneficial effects in injury repair and tissue remodelling 6 - 10 have called into question the simplistic view of senescence as only a driver of age-dependent pathologies, raising the specter that senescent cell clearance might remove useful cells in addition to detrimental ones.”
From Naturally occurring p16Ink4a-positive cells shorten healthy lifespan (2016) · cites this paper as [6]
CCN1 can trigger myofibroblast senescence through direct binding to integrin α6β1, after which senescent myofibroblasts secrete matrix-degrading enzymes and down-regulate collagen as part of the senescence-associated secretory phenotype.
“CCN1 can trigger myofibroblast senescence through direct binding to integrin α6β1, after which the senescent myofibroblasts secrete matrix‐degrading enzymes and down‐regulate collagen as part of the senescence‐associated secretory phenotype.[ 11 , 16 , 37 ]”
From Cellular communication network factor 1‐stimulated liver macrophage efferocytosis drives hepatic stellate cell activation and liver fibrosis (2022) · cites this paper as [11]
18-month-old AP-treated ATTAC mice repaired cutaneous wounds when drug administration was suspended during healing.
“Consistent with a beneficial role of senescent cells only for the duration of wound repair 6 - 8 , 18-month-old AP-treated ATTAC mice repaired cutaneous wounds when drug administration was suspended during healing (Extended Data Fig. 10ac).”
From Naturally occurring p16Ink4a-positive cells shorten healthy lifespan (2016) · cites this paper as [6]
The Methods (Animals and cutaneous wound healing) describe 12-week-old Ccn1 mice, and the Results report wound healing in those mice. Our copy does not report 18-month-old ATTAC mice, AP treatment, or suspension of treatment during healing. In the citing sentence, this citation appears to support the preceding background point about senescent cells in wound repair; the ATTAC observation is presented as the citing authors’ own Extended Data result. (LLM, conf=0.78)
Experimental — accuracy not yet measuredSASP components control multitude of functions and play key beneficial physiological roles such as accelerated wound healing by PDGF-AA and CCN1, promoting stemness and tissue plasticity, embryonic development, fibrotic scar degradation, and tumor suppression.
“SASP components control a multitude of functions and play key beneficial physiological roles such as: accelerated wound healing by secreting factors such as PDGF-AA and CCN1 (Jun and Lau, 2010; Demaria et al., 2014), promoting stemness and tissue plasticity in response to damage to maintain tissue homeostasis (Ritschka et al., 2017; Taguchi and Yamada, 2017), embryonic development (Muñoz-Espín et”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Jun and Lau, 2010
Waves of cellular senescence followed by RCD contribute to developmental embryogenesis (dispensable) and to adult tissue repair/regeneration, immunity, stem cell preservation, and oncosuppression.
“Waves of cellular senescence (followed by RCD) appear to contribute to developmental embryogenesis (although in a dispensable manner) [6, 946, 947] as well as to multiple pathophysiological processes in the adult, including tissue repair and regeneration, immunity, preservation of the stem cell compartment, and oncosuppression [948–957].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [952]
In adults, CCN1 controls inflammation, wound healing, and fibrogenesis.
“regulates inflammation, wound healing and fibrogenesis in the adult”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
CCN1 induces a DNA damage response that activates ATM, CHK1, CHK2, and p53.
“Consequently, CCN1 induces a DNA damage response, resulting in the activation of ATM, CHK1, CHK2, and p53 [2].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
In knockin mice with a CCN1 mutant unable to bind α6β1-HSPGs and defective for senescence induction, senescent cells do not accumulate in granulation tissue during wound healing, resulting in exacerbated fibrosis.
“In knockin mice that express a CCN1 mutant unable to bind α6β1–HSPGs and are thus defective for the induction of senescence, senescent cells do not accumulate in the granulation tissue during wound healing, resulting in exacerbated fibrosis [2].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
Senescent cells express an anti-fibrotic SASP that upregulates MMPs and downregulates collagen, leading to matrix degradation.
“Second, senescent cells express the anti-fibrotic SASP as described above, upregulating MMPs and downregulating collagen expression, leading to matrix degradation [2,70].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
The CCN1-induced senescence switch in later wound healing limits ECM synthesis and deposition by myofibroblasts.
“This CCN1-induced senescence switch in later stages of wound healing exerts a self-limiting effect on the synthesis and deposition of ECM by myofibroblasts in several ways (Fig. 3).”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
NOX1, but not 5-lipoxygenase, is specifically required for CCN1-induced senescence.
“Although CCN1 induces ROS through several pathways, NOX1, but not 5-lipoxygenase, is specifically required for the induction of senescence [2].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
CCN1 activates RAC1 and RAC1-dependent NOX1 during induction of fibroblast senescence.
“Through binding to integrin α6β1 and cell-surface HSPGs, CCN1 induces fibroblast senescence by activating RAC1 and the RAC1-dependent NADPH oxidase 1 (NOX1) to trigger a robust level of ROS that is sustained for many hours [2].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
As myofibroblasts proliferate in granulation tissue, CCN1 accumulates to a level high enough to drive those myofibroblasts into senescence.
“Recent studies show that, as myofibroblasts proliferate in the granulation tissue, CCN1 eventually accumulates to a sufficiently high level to drive the myofibroblasts themselves into senescence [2].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
CCN1 binding to integrin α6β1 and cell-surface HSPGs induces fibroblast senescence.
“Through binding to integrin α6β1 and cell-surface HSPGs, CCN1 induces fibroblast senescence by activating RAC1 and the RAC1-dependent NADPH oxidase 1 (NOX1) to trigger a robust level of ROS that is sustained for many hours [2].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
CCN1 triggers a robust ROS level that is sustained for many hours.
“Through binding to integrin α6β1 and cell-surface HSPGs, CCN1 induces fibroblast senescence by activating RAC1 and the RAC1-dependent NADPH oxidase 1 (NOX1) to trigger a robust level of ROS that is sustained for many hours [2].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
CCN1-induced senescent fibroblasts express elevated MMPs and downregulate collagen and TGF-β1, producing a matrix-degrading phenotype.
“Consistently, CCN1-induced senescent fibroblasts express elevated levels of MMPs and downregulate collagen and TGF-β1, thus imposing a matrix-degrading phenotype [2].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
CCN1 can cause cellular senescence.
“Another unusual activity of CCN1 as a matrix cell-adhesion molecule is the ability to induce cellular senescence [2].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
CCN1 can induce apoptosis.
“However, CCN1 can also induce apoptosis and cellular senescence [2,61,101], two well-established mechanisms of tumor suppression [155].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
CCN1 may induce senescence through a p53- and pRb-dependent pathway.
“CCN1 inhibits NSCLC cell proliferation by upregulating p53, p21, and p130/pRb [158], suggesting that CCN1 may induce senescence through a p53 and pRb-dependent pathway [2].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [2]
Senescence activation depends on the interaction of cells with ligands in the ECM.
“Senescence activation is governed by intracellular and extracellular signals and highly depends on the interaction of the cells with ligands in the ECM”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Jun and Lau, 2010
CCN1 can promote myofibroblast senescence associated with antifibrotic gene expression in skin, suggesting CCN1-mediated stromal senescence may participate in wound healing.
“CCN1 can also promote myofibroblast senescence, which is associated with the expression of antifibrotic genes in the skin, thus CCN1 mediated stromal senescence might be involved in wound healing 123”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [123]
Unlike chronic senescence, the acute induction of cellular senescence represents a transient physiological response during embryonic development and adult tissue homeostasis.
“Indeed, unlike chronic senescence (i.e., accumulation of deleterious senescent cells with aging), the acute induction of cellular senescence represents a transient physiological response during embryonic development [27,28] and adult tissue homeostasis (e.g., to facilitate tissue repair after liver damage, in skin fibrosis, and wound healing) [29,30,31].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [30]
The SASP is involved in valuable physiological processes such as promoting tissue repair, fine-tuning development of embryonic structures, and stimulating immune surveillance.
“Furthermore, the SASP is involved in valuable physiological processes such as promoting tissue repair,18–20 fine-tuning the development of embryonic structures,21–23 and stimulating immune surveillance.24,25”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [18]
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- Authors
- Jun, J.-I., & Lau, L. F.
- Affiliations
- University of Illinois Chicago (US)
- Corresponding author
- Lau, Lester F.
- ORCID
- Lau, Lester F.
- Venue
- Nature Cell Biology
- Published
- 2010-06-06
- Volume
- 12
- Issue
- 7
- Pages
- 676-685
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC2919364
- OpenAlex
- W2052388837
- Semantic Scholar
- 021909655ca17d7829e0033f9477ac406f78e186
- Cited by
- 998
- References
- 72
- Citations by year
- 2026: 62 · 2025: 51 · 2024: 82 · 2023: 87 · 2022: 79 · 2021: 93 · 2020: 83 · 2019: 72 · 2018: 65 · 2017: 56 · 2016: 62 · 2015: 53 · 2014: 55 · 2013: 38 · 2012: 29
- FWCI
- 12.50
- Type
- journal article
- Language
- en
- Update notices
- erratum (2010-12-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA046565)
- National Institute of General Medical Sciences (R01GM078492)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- CYR61, cellular senescence, fibroblast senescence, skin wound healing, fibrosis, alpha6beta1 integrin, heparan sulfate proteoglycans, DNA damage response, p53, reactive oxygen species, granulation tissue
- MeSH terms
- Animals, Cell Line, Collagen, Fibroblasts, Humans, Mice, Inbred C57BL, Microscopy, Fluorescence, Wound Healing, Blotting, Western, Cellular Senescence, Reactive Oxygen Species, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Cell Proliferation, Mice, Cysteine-Rich Protein 61
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